Parasitic protozoa are parasites on a broad range of animals inclusive of mammals, birds, fishes and insects. The parasitic protozoa establish themselves in the internal organs or the external organs such as the skin and eye of the host animal. As such, these parasites give the hosts serious lesion and often infect the producing farmers of domestic animals, poultry and fish, causing great economic damage. Coccidiosis, which is one of the diseases causing the most serious economic damage to breeding, is mainly caused by several kinds of protozoa of the genus Eimeria, such as E. tenella, E. necatrix, E. acervulira, E. maxima, E. brunetti and E. mivati.
For example, E. tenella parasitizes the intestinal inner walls, such as that of the caecum, and often inflicts fatal damage on the host. Thus, the E. tenella infection produces several manifestations such as extensive erosion, inflammation and hemorrhage of the intestinal paries due to the development of the protozoa, caecal blood retention, and, hence, anaemia, retardation of growth or death of the host. Endoparastic protozoa are usually transmitted orally and as to coccidiosis in particular, even intensive disinfection with potassium dichromate solution fails to kill the oocysts. Moreover, since their life cycle is as short as about 7 days, one engaged in large-scale animal farming has to face the outbreak and spread of disease without an effective countermeasure.
As far as fishes are concerned, ectoparasitic protozoa are serious problems of concern. Their parasitization damages the host's skin and gills, weakens the resistance of the host fish to infections and may occasionally be fatal. In large-scale fish farming, parasitic protozoa spread among the whole fish population on a farm and the resulting economic loss is too large to be overlooked.
A similar situation prevails for insects. Taking bees as an example, parasitic protozoan represented by Nosema apis are doing a great deal of harm to apiculture all over the world. Nosema apis destroys the internal organs to debilitate the host bee, and the host with accordingly decreased resistance tends to succumb to various other diseases.
Several drugs against parasitic protozoa have been proposed but most of them are limited in the indication and spectrum of activity and even protozoa with acquired resistance to certain drugs are already known. Furthermore, the weak activity of these drugs requires massive doses so that none are satisfactory enough from both economic and ecological points of view. Therefore, development of drugs which can be used broadly with sufficient effectiveness for control of such parasites in animals, poultry, fishes and insects are awaited in earnest.
As such drugs, 2-phenyl-6-azauracil derivatives were found to have an anticoccidial activity [J. Med. Chem. 22, 1483 (1979)] and a variety of 6-azauracil derivatives were synthesized and tested. However, these compounds were found to be teratogenic and, therefore, could not find application in the field. As compounds which overcame the problems related to the teratogenicity, 1,2,4-triazinediones are in use in some European countries, Australia and Hungary or South Africa as anticoccidial drugs. However, since these compounds remain in the body in long time their use is critically restricted and even banned in several countries including Japan.
In view of above state of the art, the present inventors have researched and found that a series of novel triazine derivatives have excellent activity against parasitic protozoa. Further intensive research led them to the discovery that this series of derivatives is suited for the control of a broad spectrum of parasitic protozoa encountered in rearing and raising animals such as mammals, birds, fish and insects under the usual husbandry and breeding conditions, are of low toxicity to animals, and exhibit remarkably high antiprotozoal activity even against strains resistant to the drugs heretofore available. This first embodiment has been brought into being on the basis of the above findings.